Molecule Information

General Information of the Molecule (ID: Mol00409)

• Name: Homeodomain-interacting protein kinase 3 (HIPK3) ,Homo sapiens
• Synonyms: Androgen receptor-interacting nuclear protein kinase; ANPK; Fas-interacting serine/threonine-protein kinase; FIST; Homolog of protein kinase YAK1; DYRK6; FIST3; PKY
• Molecule Type: Protein
• Gene Name: HIPK3
• Gene ID: 10114
• Location: chr11:33256672-33357023[+]
• Sequence:
  MASQVLVYPPYVYQTQSSAFCSVKKLKVEPSSCVFQERNYPRTYVNGRNFGNSHPPTKGS
  AFQTKIPFNRPRGHNFSLQTSAVVLKNTAGATKVIAAQAQQAHVQAPQIGAWRNRLHFLE
  GPQRCGLKRKSEELDNHSSAMQIVDELSILPAMLQTNMGNPVTVVTATTGSKQNCTTGEG
  DYQLVQHEVLCSMKNTYEVLDFLGRGTFGQVVKCWKRGTNEIVAIKILKNHPSYARQGQI
  EVSILARLSTENADEYNFVRAYECFQHRNHTCLVFEMLEQNLYDFLKQNKFSPLPLKVIR
  PILQQVATALKKLKSLGLIHADLKPENIMLVDPVRQPYRVKVIDFGSASHVSKTVCSTYL
  QSRYYRAPEIILGLPFCEAIDMWSLGCVIAELFLGWPLYPGALEYDQIRYISQTQGLPGE
  QLLNVGTKSTRFFCKETDMSHSGWRLKTLEEHEAETGMKSKEARKYIFNSLDDVAHVNTV
  MDLEGSDLLAEKADRREFVSLLKKMLLIDADLRITPAETLNHPFVNMKHLLDFPHSNHVK
  SCFHIMDICKSHLNSCDTNNHNKTSLLRPVASSSTATLTANFTKIGTLRSQALTTSAHSV
  VHHGIPLQAGTAQFGCGDAFQQTLIICPPAIQGIPATHGKPTSYSIRVDNTVPLVTQAPA
  VQPLQIRPGVLSQTWSGRTQQMLVPAWQQVTPLAPATTTLTSESVAGSHRLGDWGKMISC
  SNHYNSVMPQPLLTNQITLSAPQPVSVGIAHVVWPQPATTKKNKQCQNRGILVKLMEWEP
  GREEINAFSWSNSLQNTNIPHSAFISPKIINGKDVEEVSCIETQDNQNSEGEARNCCETS
  IRQDSDSSVSDKQRQTIIIADSPSPAVSVITISSDTDEEETSQRHSLRECKGSLDCEACQ
  STLNIDRMCSLSSPDSTLSTSSSGQSSPSPCKRPNSMSDEEQESSCDTVDGSPTSDSSGH
  DSPFAESTFVEDTHENTELVSSADTETKPAVCSVVVPPVELENGLNADEHMANTDSICQP
  LIKGRSAPGRLNQPSAVGTRQQKLTSAFQQQHLNFSQVQHFGSGHQEWNGNFGHRRQQAY
  IPTSVTSNPFTLSHGSPNHTAVHAHLAGNTHLGGQPTLLPYPSSATLSSAAPVAHLLASP
  CTSRPMLQHPTYNISHPSGIVHQVPVGLNPRLLPSPTIHQTQYKPIFPPHSYIAASPAYT
  GFPLSPTKLSQYPYM
• 3D-structure: PDB ID: 7O7I; Classification: Transferase; Method: X-ray diffraction; Resolution: 2.50 Å
• Function: Serine/threonine-protein kinase involved in transcription regulation, apoptosis and steroidogenic gene expression. Phosphorylates JUN and RUNX2. Seems to negatively regulate apoptosis by promoting FADD phosphorylation. Enhances androgen receptor-mediated transcription. May act as a transcriptional corepressor for NK homeodomain transcription factors. The phosphorylation of NR5A1 activates SF1 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. In osteoblasts, supports transcription activation: phosphorylates RUNX2 that synergizes with SPEN/MINT to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE).
• Uniprot ID: HIPK3_HUMAN
• Ensembl ID: ENSG00000110422
• HGNC ID: HGNC:4915

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Apalutamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Prostate cancer [ICD-11: 2C82.0] [1]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PNT1A cells; Prostate; Homo sapiens (Human); CVCL_2163
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [21]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

Disease Class: Prostate cancer [ICD-11: 2C82.0] [1]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [22]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

Disease Class: Prostate cancer [ICD-11: 2C82.0] [1]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [23]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

Disease Class: Prostate cancer [ICD-11: 2C82.0] [1]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [24]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Osteosarcoma [ICD-11: 2B51.0] [2]

• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Osteosarcoma [ICD-11: 2B51.0] [2]

• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.

Methotrexate

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Osteosarcoma [ICD-11: 2B51.0] [2]

• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Sensitive Drug: Methotrexate
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.

discontinued Drug(s) 1 drug(s) in total

IACS-010759

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Prostate cancer [ICD-11: 2C82.0] [1]

• Metabolic Type: Mitochondrial metabolism
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: IACS-010759
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PNT1A cells; Prostate; Homo sapiens (Human); CVCL_2163
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [25]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

Disease Class: Prostate cancer [ICD-11: 2C82.0] [1]

• Metabolic Type: Mitochondrial metabolism
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: IACS-010759
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [26]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

Disease Class: Prostate cancer [ICD-11: 2C82.0] [1]

• Metabolic Type: Mitochondrial metabolism
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: IACS-010759
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [27]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

Disease Class: Prostate cancer [ICD-11: 2C82.0] [1]

• Metabolic Type: Mitochondrial metabolism
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: IACS-010759
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [28]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

References

• Ref 1: Mitochondrial Elongation and ROS-Mediated Apoptosis in Prostate Cancer Cells under Therapy with Apalutamide and Complex I Inhibitor. Int J Mol Sci. 2024 Jun 25;25(13):6939.
• Ref 2: miR-382 inhibits tumor growth and enhance chemosensitivity in osteosarcoma. Oncotarget. 2014 Oct 15;5(19):9472-83. doi: 10.18632/oncotarget.2418.